7. Project Summary/Abstract The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision-making in multicellular organisms. Despite their impressive role in a broad range of maladies including cancer and degenerative diseases, Wnt molecules and the cellular responses that they regulate have largely been refractory to selective chemical manipulation. In the last few years, my research group has taken a leadership role in efforts to identify novel points of chemical intervention in Wnt-related diseases. Our discovery that the Wnt acyltransferase Porcupine (Porcn) is highly druggable and a chemical vulnerability in Wnt-mediated communication has laid open new approaches to achieving regenerative medicine goals premised upon modulating Wnt signaling. In this proposal, we outline experiments that are essential to the development of Porcn inhibitors as first-in-class anti-fibrotic agents for use following myocardial infarction. These studies will delineate the mechanistic basis underlying the pro-regenerative activity of Porcn inhibitors and define an optimal drug delivery regiment that minimizes chemical exposure time and maximizes regenerative outcome in heart tissue. The data returned from the completion of these studies will facilitate the development of a more general playbook for the use of Wnt pathway antagonists in promoting adult tissue regeneration.